Novel processes for the preparation of bicyclic aminoalcohols

ABSTRACT

The present invention provides a process for the preparation of a bicyclic aminoalcohol which comprises reacting a starting compound, nopinone (I), with XCH 2 COOR 1  wherein X is halogen, and R 1  is alkyl, in the presence of an additive and a base to produce a compound (II), converting it to oxime derivative (III), and reducing it with an aluminum hydride.

TECHNICAL FIELD

[0001] The present invention relates to processes for the preparation ofbicyclic aminoalcohols.

BACKGROUND ART

[0002] The following scheme is disclosed in Chem. Pharm. Bull., 37(6),1524-1533 (1989) as processes for the preparation of a bicyclicaminoalcohol (IV).

[0003] A starting material, myrtenol, is reacted with ethyl orthoformateto give an exomethylene derivative. The exomethylene derivative isoxidized by ozone to give a ketone derivative, compound (II-1), which isfurther reacted with O-methylhydroxyamine to give an O-methyloximederivative, compound (III-1). The obtained O-methyloxime derivative isreduced in n-propanol with metallic sodium to give a bicyclicaminoalcohol, compound (IV).

[0004] It is disclosed in the above document that alkylation ofnopinone, compound (I), gives a mixture of the starting material, adi-substituted product and a mono-substituted product as shown below.Moreover, the mono-substituted product is disclosed as a mixture of twostereo isomers.

DISCLOSURE OF INVENTION

[0005] There are some problems in the above process for the preparationof the bicyclic aminoalcohol that the starting material, myrtenol, isexpensive and not preferable in view of supply. Thus, another processfor the preparation of the ketone derivative, compound (II-1), isdesired. In the above method, the purity of the bicyclic aminoalcohol(compound (IV)) obtained through reduction of the O-methyloximederivative (compound (III-1)) is not so high. When the bicyclicaminoalcohol is crystallized and purified as a salt with benzoic acid,the yield is only 39.6%.

[0006] A benzothiophene carboxamide derivative, compound (VIII):

[0007] wherein R³ is hydrogen, alkyl, acyl, alkylsulfonyl orarylsulfonyl, R⁴ is hydrogen or alkyl, and a double bond represents E-or Z-configuration, is a high selective PGD2 receptor antagonist. WO98/25919 discloses the following process for the preparation of thecompound (VIII).

[0008] wherein R³ is hydrogen, alkyl, acyl, alkylsulfonyl orarylsulfonyl, R⁴ is hydrogen or alkyl, and a double bond represents E-or Z-configuration.

[0009] The bicyclic aminoalcohol of the formula (IV):

[0010] is useful as an intermediate of the compound (VIII) and should beprepared at a low cost and stably provided.

[0011] But, a prior art of process for the preparation of the bicyclicaminoalcohol (IV) has the above problems.

[0012] On the other hand, as shown below, a method using an alkalinemetal- or alkaline earth metal-substituted borohydride in the presenceof a Lewis acid is known as a reduction of an O-methyloxime derivative(compound (III-1)) to a bicyclic aminoalcohol (compound (IV)).

[0013] But the above method using such borohydrides is accompanied withproduction of diborane, so this method has a problem in view of safetyfor an industrial process.

[0014] The present inventors have found out a process for thepreparation of the ketone derivative (compound (II)) from nopinone(compound (I)) and a novel process for the reduction of theO-methyloxime derivative or a more inexpensive oxime derivative(compound (III)) to the bicyclic aminoalcohol (compound (IV)), todevelop a safe process for the preparation of the bicyclic aminoalcohol.

[0015] The present invention provides;

[0016] 1) a process for the preparation of a compound (II):

[0017] wherein R¹ is alkyl, which comprises reacting a compound (I):

[0018] with XCH₂COOR¹ wherein X is halogen, and R¹ is as defined abovein the presence of an additive and a base,

[0019] 2) a process for the preparation of a compound (IV):

[0020] which comprises reducing a compound (III):

[0021] wherein R¹ is as defined above, and R² is hydrogen or alkyl, withan aluminum hydride,

[0022] 3) a process for the preparation of a compound (IV):

[0023] which comprises reacting a compound (II):

[0024] wherein R¹ is as defined above, with NH₂OR² wherein R² is asdefined above to give a compound (III):

[0025] wherein R¹ and R² are as defined above, and reducing the compound(III) with an aluminum hydride,

[0026] 4) a process for the preparation of a compound (III):

[0027] wherein R¹ and R² are as defined above, which comprises preparinga compound (II):

[0028] wherein R¹ is as defined above, through the process according tothe above 1), and reacting the compound (II) with NH₂OR² wherein R² isas defined above,

[0029] 5) a process for the preparation of a compound (IV):

[0030] which comprises preparing a compound (III):

[0031] wherein R¹ and R² are as defined above through the processaccording to the above 4), and reducing the compound (III) with analuminum hydride,

[0032] 6) the process according to the above 2), 3) or 5) wherein thealuminum hydride is prepared by reacting a Lewis acid with lithiumaluminum hydride or reacting concentrated sulfuric acid with lithiumaluminum hydride,

[0033] 7) a process for the preparation of a compound (IX):

[0034] wherein R⁵ each is independently alkyl, which comprises reactinga compound (I):

[0035] with (R⁵)₃SiX wherein R⁵ is as defined above, and X is halogen,in the presence of a base,

[0036] 8) a process for the preparation of a compound (X):

[0037] wherein R⁶ each is independently alkyl, which comprises reactinga compound (IX):

[0038] wherein R⁵ each is independently alkyl, with CH₂═CHOR⁶ wherein R⁶is as defined above in the presence of ceric ammonium nitrate (IV) in asolvent of R⁶OH wherein R⁶ is as defined above,

[0039] 9) a process for the preparation of a compound (X):

[0040] wherein R⁶ is as defined above, which comprises preparing acompound (IX):

[0041] wherein R⁵ is as defined above through the process according tothe above 7), and reacting the compound (IX) with CH₂═CHOR⁶ wherein R⁶is as defined above in the presence of ceric ammonium nitrate (IV) in asolvent of R⁶OH wherein R⁶ is as defined above,

[0042] 10) a process for the preparation of a compound (VI):

[0043] wherein R³ is hydrogen, alkyl, acyl, alkylsulfonyl orarylsulfonyl, which comprises preparing a compound (IV):

[0044] through the process according to any one of the above 2), 3), 5)and 6), and reacting the compound (IV) or its salt with a compound (V):

[0045] wherein R³ is as defined above or its reactive derivative,

[0046] 11) a process for the preparation of a compound (VII):

[0047] wherein R³ is as defined above, which comprises preparing acompound (VI):

[0048] wherein R³ is as defined above through the process according tothe above 10), and oxidizing the compound (VI),

[0049] 12) a process for the preparation of a compound (VII):

[0050] wherein R³ is as defined above, which comprises preparing acompound (X):

[0051] wherein R⁶ is as defined above through the process according tothe above 8) or 9), reacting the compound (X) with NH₂OR² wherein R² isas defined above to give a compound (XI):

[0052] wherein R² and R⁶ are as defined above, reducing the compound(XI) to give a compound (XII):

[0053] wherein R⁶ is as defined above, reacting the compound (XII) witha compound (V):

[0054] wherein R³ is as defined above or its reactive derivative to givea compound (XIII):

[0055] wherein R³ and R⁶ are as defined above, and reacting the compound(XIII) with an acid,

[0056] 13) a process for the preparation of a compound (VIII):

[0057] wherein R³ is as defined above, R⁴ is hydrogen or alkyl, and adouble bond represents E- or Z-configuration, a pharmaceuticallyacceptable salt or hydrate thereof, which comprises preparing a compound(VII):

[0058] wherein R³ is as defined above through the process according tothe above 11) or 12), reacting the compound (VII) with an ylide of theformula: Ph₃P═CH(CH₂)₃COOR⁴ wherein R⁴ is as defined above, and ifdesired, deprotecting.

[0059] The term “alkyl” includes straight or branched C1 to C6 alkyl,for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl,n-hexyl, isohexyl or the like. Preferred is methyl or ethyl.

[0060] The term “acyl” includes carbonyl substituted with hydrogen orthe above alkyl, for example, formyl, acetyl, propionyl, butyryl,isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl or the like.Preferred is formyl or acetyl.

[0061] The term “alkylsulfonyl” includes sulfonyl substituted with theabove alkyl, for example, methanesulfonyl, ethanesulfonyl or the like.

[0062] The term “arylsulfonyl” includes sulfonyl substituted with aryl.The term “aryl” includes a monocyclic aromatic carbocyclic group orpolycyclic aromatic carbocyclic group, for example, phenyl, naphthyl orthe like. Aryl may be substituted with the above alkyl. Examples ofarylsulfonyl include benzenesulfonyl, p-toluenesulfonyl or the like.

[0063] The term “halogen” means fluoro, chloro, bromo or iodo.

BEST MODE FOR CARRYING OUT THE INVENTION

[0064]

[0065] wherein R¹ is alkyl, R² is hydrogen or alkyl, and X is halogen.

[0066] Step 1

[0067] This step shows a process for the preparation of a ketonederivative (compound (II)) from nopinone (compound (I)). Amono-substituted derivative (compound (II)) can be obtained in highyield by reacting a compound (I) with XCH₂COOR¹ wherein X and R¹ aredefined above in the presence of an additive and a base, withoutproducing a mixture of the starting material, a di-substitutedderivative and a mono-substituted derivative as shown in the abovedocument.

[0068] An additive includes a reagent controlling the stereochemistry,such as N,N,N′,N′-tetramethylethylenediamine (TMEDA),hexamethylphosphoramide (HMPA), N,N′-dimethlpropyleneurea (DMPU),1,3-dimethyl-2-imidazolidinone (DMI) or the like. Preferred isN,N′-dimethlpropyleneurea (DMPU) or 1,3-dimethyl-2-imidazolidinone(DMI). The amount of an additive is preferably 0.01 to 10.0 moleequivalent, more preferably 0.5 to 2.0 mole equivalent, and especially1.0 to 1.5 mole equivalent to the compound (I).

[0069] A base includes a lithiation reagent such as lithiumdiisopropylamide(LDA), n-butyllithium or the like. Preferred is lithiumdiisopropylamide(LDA). A commercially available LDA may be used. LDA maybe prepared by reacting diisopropylamine with n-butyllithium when it isused. The amount of a base is preferably 1.0 to 10.0 mole equivalent,more preferably 1.0 to 3.0 mole equivalent, and especially 1.0 to 1.5mole equivalent to the compound (I).

[0070] XCH₂COOR¹ wherein X is halogen, and R¹ is alkyl, includes ethylbromoacetate, methyl bromoacetate or the like. Preferred is ethylbromoacetate. The amount of XCH₂COOR¹ wherein X and R¹ are as definedabove is preferably 1.0 to 10.0 mole equivalent, more preferably 1.0 to5.0 mole equivalent, and especially 2.0 to 3.0 mole equivalent to thecompound (I).

[0071] The amount of XCH₂COOR¹ wherein X and R¹ are as defined above ispreferably larger than that of a base. A preferred amount is: additive1.0 mole equivalent, base 1.0 to 1.2 mole equivalent and XCH₂COOR¹ 2.0to 3.0 mole equivalent to the compound (I).

[0072] It is preferred in this process that XCH₂COOR¹ is added to amixture of the compound (I), an additive and a base. The compound (I),additive and base may be added in any order. For example, the additioncan be performed in the order of compound (I), additive and base, or theorder of base, additive and compound (I).

[0073] The reaction temperature is −100 to 100° C., preferably −70° C.to room temperature.

[0074] The reaction time is 0.5 to 50 hours, preferably 1 to 24 hours.

[0075] The reaction solvent includes an ether derivative (e.g., ethylether, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, diethylene glycoldimethyl ether or the like), a hydrocarbon derivative (e.g., toluene,xylene) or a mixed solvent of an ether derivative and a hydrocarbonderivative.

[0076] Step 2

[0077] This process shows a process for the preparation of an oximederivative (compound (III)) from a ketone derivative (compound (II)). Acompound (III) can be prepared by reacting a compound (II) with NH₂OR²wherein R² is as defined above.

[0078] NH₂OR² wherein R² is as defined above includes hydroxylamine,O-methylhydroxylamine or the like.

[0079] The reaction temperature is 0 to 150° C., preferably 50 to 100°C. When NH₂OR² is hydroxylamine, the reaction is preferably carried outunder 70° C. because the reaction at high temperature causes anisomerization.

[0080] The reaction time is 0.5 to 50 hours, preferably 1 to 24 hours.

[0081] Step 3

[0082] This step includes a process for the preparation of a bicyclicaminoalcohol (compound (IV)) from an oxime derivative (compound (III)).The bicyclic aminoalcohol (compound (IV)) can be prepared in high yieldwith high stereo selectivity and safety by reducing the oxime and esterparts of the oxime derivative (compound (III)) with an aluminum hydrideat the same time.

[0083] An aluminum hydride can be prepared by reacting a Lewis acid orconcentrated sulfuric acid with lithium aluminum hydride. Thepreparation can be carried out in the presence of a compound (III) orpreferably before the addition of a compound (III).

[0084] A Lewis acid includes a halogenated compound such as halogenatedtin, halogenated zinc, halogenated aluminum, halogenated titanium,halogenated boron, halogenated beryllium, halogenated zirconium,halogenated nickel or the like (e.g., stannous chloride, stannicchloride, aluminum chloride (AlCl₃), zinc chloride (ZnCl₂), berylliumchloride (BeCl₂), titanium tetrachloride, boron trifluoride, zirconiumtetrachloride, nickel dichloride). Preferred is aluminum chloride, zincchloride or beryllium chloride.

[0085] For example, an aluminum hydride (AlH₃) is produced in accordancewith the following formulae.

3LiAlH₄+AlCl₃→3LiCl+4AlH₃

2LiAlH₄+H₂SO₄→Li₂SO₄+2AlH₃+2H₂

2LiAlH₄+BeCl₂→Li₂BeH₂Cl₂+2AlH₃

2LiAlH₄+ZnCl₂→2LiCl+ZnH₂+2AlH₃

[0086] The reaction solvent includes ether derivatives (e.g.,ethylether, tetrahydrofuran, 1,2-dimethoxyethane, dioxane, diethyleneglycol dimethyl ether), hydrocarbon derivatives (e.g., toluene, xylene),a mixed solvent of ether derivatives and hydrocarbon derivatives.Preferred is tetrahydrofuran.

[0087] The amount of aluminum hydride is preferably 1.0 to 10.0 moleequivalent, more preferably 2.0 to 10.0 mole equivalent, and especially2.0 to 5.0 mole equivalent to the compound (III).

[0088] In the preparation of aluminum hydride, the amount of a Lewisacid, which depends on the kind of Lewis acid, is preferably 0.25 to 2.5mole equivalent, more preferably 0.5 to 2.5 mole equivalent, andespecially 0.5 to 1.25 mole equivalent to the compound (III). In theabove case, the amount of lithium aluminum hydride is preferably 0.75 to7.5 mole equivalent, more preferably 1.5 to 3.75 mole equivalent to thecompound (III).

[0089] When concentrated sulfuric acid is used for the preparation ofaluminum hydride, the amount of concentrated sulfuric acid is preferably0.5 to 5.0 mole equivalent, more preferably 1.0 to 5.0 mole equivalent,especially 1.0 to 2.5 mole equivalent to the compound (III). In theabove case, the amount of lithium aluminum hydride is preferably 1.0 to10.0 mole equivalent, more preferably 2.0 to 5.0 mole equivalent.

[0090] The amount of aluminum hydride is preferably 4.0 mole equivalentto the compound (III). Preferably, the amount of lithium aluminumhydride is 3.0 to 4.0 mole equivalent, and that of aluminum chloride orconcentrated sulfuric acid is 1.0 to 2.0 mole equivalent.

[0091] The procedure is concretely explained below. Two or more moleequivalent of lithium aluminum hydride to the compound (III) is added toa solvent at 0° C. to room temperature. 0.33 to 0.5 mole equivalent of aLewis acid or concentrated sulfuric acid is added thereto. In this case,the Lewis acid or concentrated sulfuric acid can be dissolved in thesolvent in advance. To this suspension is added a starting material (anoxime derivative, compound (III)) dissolved in double or more volume ofa solvent. The oxime derivative (compound (III)), lithium aluminumhydride, Lewis acid or concentrated sulfuric acid can be added in anyorder. Then, the reaction mixture is stirred at 0 to 150° C. for a fewminutes to hours. The mixture is mixed with water, and a diluted mineralacid (e.g., diluted hydrochloric acid), then stirred for decomposingexcess of lithium aluminum hydride or aluminum hydride. The reactionmixture may be poured into to the diluted mineral acid.

[0092] Then the mixture is neutralized with an alkali (e.g., sodiumhydroxide), extracted with an organic solvent (e.g., ethyl acetate) andevaporated to give a bicyclic aminoalcohol (compound (IV)). Ifnecessary, the purification of bicyclic aminoalcohol (compound (IV)) canbe carried out by forming a crystalline salt with an appropriate acid(e.g., benzoic acid) and neutralizing with an alkali.

[0093] The desired compound, bicyclic aminoalcohol (compound (IV)) canbe prepared in high yield with high stereo selectivity by the abovemethod.

[0094] The process for the preparation of bicyclic aminoalcoholdescribed above is novel and useful. As shown below, a combination ofthis process and the process for the preparation of the final targetcompound (compound (VIII)) contributes to safe and efficient productionof compound (VIII).

[0095] wherein R³ is hydrogen, alkyl, acyl, alkylsulfonyl orarylsulfonyl, R⁴ is hydrogen or alkyl, and a double bond represents E-or Z-configuration.

[0096] Step 4

[0097] This scheme shows a process for the preparation of an amidederivative (VI) which comprises acylating a bicyclic aminoalcohol (IV)or its salt with a carboxylic acid (V) or its reactive derivative.

[0098] The salt of bicyclic aminoalcohol (IV) includes a salt with anorganic acid (e.g., benzoic acid) or an inorganic acid (e.g.,hydrochloric acid, sulfuric acid).

[0099] The carboxylic acid (V) used in the acylation can be synthesizedin accordance with a known method in literatures [for example,Nippon-Kagaku Zasshi vol. 88, No. 7, 758-763 (1967); Nippon-KagakuZasshi vol. 86, No. 10, 1067-1072 (1965); J. Chem. Soc. (C).1899-1905(1967); J. Heterocycle. Chem. vol.10, 679-681(1973)].

[0100] The term “reactive derivative” of carboxylic acid (V) refers tocorresponding acid halides (e.g., chloride, bromide, iodide), acidanhydrides (e.g., mixed acid anhydride with formic acid or acetic acid),activated esters (e.g., succinimide ester), and the like, and includesacylating agents generally used for the acylation of amino group. Forexample, to obtain acid halides, a carboxylic acid is reacted withthionyl halide (e.g., thionyl chloride), phosphorous halide (e.g.,phosphorous trichloride, phosphorous pentachloride), oxalyl halide(e.g., oxalyl chloride), or the like, according to a known method (e.g.,Shin-jikken Kagaku Koza, vol. 14, p. 1787 (1978); Synthesis852-854(1986); Shin-jikken Kagaku Koza vol. 22, p. 115 (1992)).

[0101] The acylation can be carried out under ordinary conditions usedfor the acylation of amino group. For example, when a carboxylic acidhalide is used, the reaction is carried out according to a methodcommonly known as “Schotten-Baumann reaction”. In general, carboxylicacid halide is added dropwise to an aqueous alkaline solution of aminewith stirring and under cooling while removing the generating acid withalkali. Alternatively, when a carboxylic acid is used as a free acid nota reactive derivative, the reaction can be conducted conventionally inthe presence of a coupling agent generally used in the coupling reactionbetween an amine and a carboxylic acid, such asdicyclohexylcarbodiimide(DCC),1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide orN,N′-carbonyldiimidazole.

[0102] Step 5

[0103] This step is related to the oxidation of an alcohol (VI) to analdehyde (VII). Such a reaction can be conducted by using an oxidizingagent of chromium oxide type such as Jones reagent, Collins reagent orpyridinium chlorochromate. Further, oxidation with manganese dioxide orSwern oxidation with dimethyl sulfoxide are also applicable.

[0104] The other oxidation can be carried out with an oxidizing agent(s)such as halo oxoacid in the presence of TEMPO. Examples of TEMPO include2,2,6,6-tetramethyl-piperidine-1-oxyl,4-methoxy-2,2,6,6-tetramethylpiperidine-1-oxyl,4-acetylamino-2,2,6,6-tetramethylpiperidine-1-oxyl,4-benzoyloxy-2,2,6,6-tetramethylpiperidine-1-oxyl, and4-cyano-2,2,6,6-tetramethylpiperidine-1-oxyl. Examples of halo oxoacidinclude sodium hypochlorite, sodium hypobromite, sodium bromite andhigher bleaching powder.

[0105] Step 6

[0106] This step is related to the formation of a double bond byreacting an aldehyde (compound (VII)) with an ylide (Ph₃P═CH(CH₂)₃COOR⁴wherein R⁴ is hydrogen or alkyl).

[0107] The reaction forming a double bond can be carried out in aconventional manner for Wittig reaction. The ylides used in the reactioncan be synthesized, in the presence of a base, from a phosphonium saltwhich has been synthesized from triphenylphosphine and an alkyl halidehaving a desired alkyl group to be condensed, for example,5-bromopentanoic acid. Preferred is Ph₃P═CH(CH₂)₃COOH.

[0108] Examples of a base include dimsyl sodium, dimsyl potassium,sodium hydride, n-butyl lithium, potassium t-butoxide and lithiumdiisopropylamide. The reaction is accomplished within several hours atroom temperature in a solvent such as ether, tetrahydrofuran, n-hexane,1,2-dimethoxyethane or dimethyl sulfoxide.

[0109] The double bond of the alkenylene side chain (5-heptenylenechain) on a compound (VIII) may be in the E- or Z-configuration.

[0110] A compound wherein R³ is hydrogen can be prepared by deprotectingR³ under an acidic condition (e.g., hydrochloric acid, sulfuric acid,boron tribromide), a neutral condition (e.g., trimethylsilyl iodide) ora basic condition (e.g., sodium hydroxide, potassium hydroxide, bariumhydroxide). The reaction is accomplished within several tens minutes toseveral hours with heating in a solvent such as methanol-water,ethanol-water, acetone-water, acetonitrile-water, or the like,preferably dimethyl sulfoxide-water. The OR³ may be positioned at any of4-, 5-, 6- and 7-positions and preferably at 5-position.

[0111] The compound (VIII) prepared from the above processes can beformed into a salt. Examples of the salt include alkali metal salts suchas lithium salt, sodium salt or potassium salt and the like, alkaliearth metal salts such as calcium salt and the like, ammonium salt,salts with an organic base such as tromethamine, trimethylamine,triethylamine, 2-aminobutane, tert-butylamine, diisopropylethylamine,n-butylmethylamine, n-butyldimethylamine, tri-n-butylamine,cyclohexylamine, dicyclohexylamine, N-isopropylcyclohexylamine,furfurylamine, benzylamine, methylbenzylamine, dibenzylamine,N,N-dimethylbenzylamine, 2-chlorobenzylamine, 4-methoxybenzylamine,1-naphthalenemethylamine, diphenylbenzylamine, triphenylamine,1-naphthylamine, 1-aminoanthracene, 2-aminoanthracene,dehydroabiethylamine, N-methylmorpholine or pyridine, or amino acidsalts such as lysine salt or arginine salt.

[0112] A hydrate of a compound (VIII) or its salt includes monohydrate,dihydrate, monohydrate of sodium salt, monohydrate of half calcium salt,dihydrate of half calcium salt or the like.

[0113] wherein R² is hydrogen or alkyl, R⁵ each is independently alkyl,R⁶ is alkyl, R³ is hydrogen, alkyl, acyl, alkylsulfonyl or arylsulfonyl,and X is halogen.

[0114] Step 7

[0115] This step is related to the preparation of a silyl ether(compound (IX)) by reacting nopinone (compound (I)) with a compound ofthe formula: (R⁵)₃SiX wherein R⁵ each is independently alkyl, and X ishalogen, in the presence of a base.

[0116] A base includes a lithiation agent such as lithiumdiisopropylamide, lithium bis(trimethylsilyl)amide. The amount of a baseis 1.0 to 2.0 mole equivalent, especially 1.0 to 1.5 mole equivalent tothe compound (I).

[0117] A compound of the formula: (R⁵)₃SiX includeschlorotrimethylsilane, bromotrimethylsilane, chlorotriethylsilane or thelike. The amount of a compound of the formula: (R⁵)₃SiX is 1.0 to 2.0mole equivalent, especially 1.0 to 1.5 mole equivalent to the compound(I).

[0118] The present reaction is accomplished within several hours toseveral tens hours under −100° C. to 100° C., especially −70° C. to roomtemperature.

[0119] In the present step, a compound (I), a base and a compound of theformula: (R⁵)₃SiX can be added in any order. Preferably, a base is addedunder cooling to compound (I), and the mixture is stirred for severalminutes to several hours, followed by adding a compound of the formula:(R⁵)₃SiX. After the addition of a base, the mixture can be warmed up toapproximately 0° C., cooled, and mixed with a compound of the formula:(R⁵)₃SiX.

[0120] The reaction solvent includes a non-polar solvent such astetrahydrofuran, dioxane, diethyl ether or the like.

[0121] Step 8

[0122] This step is related to the preparation of a compound (X) byreacting a silylether derivative (compound (IX)) with a compound of theformula: CH₂═CHOR⁶ wherein R⁶ is alkyl, in the presence of cericammonium nitrate (IV) in a solvent of R⁶OH wherein R⁶ is as definedabove.

[0123] A compound of the formula: CH₂═CHOR⁶ includes methyl vinyl ether(R⁶ is methyl), ethyl vinyl ether (R⁶ is ethyl), n-propyl vinyl ether(R⁶ is n-propyl), n-butyl vinyl ether (R⁶ is n-butyl), vinyl acetate (R⁶is acetyl) or the like. The amount of a compound of the formula:CH₂═CHOR⁶ is 1.0 to 30.0 mole equivalent, especially 10.0 to 20.0 moleequivalent to the compound (IX).

[0124] R⁶OH includes an alchol having R⁶ corresponding to R⁶ of acompound of the formula: CH₂═CHOR⁶ used in the present step. When acompound of the formula: CH₂═CHOR⁶ is methyl vinyl ether, ethyl vinylether, n-propyl vinyl ether and n-butyl vinyl ether, R⁶OH is methanol,ethanol, n-propanol and n-butanol, respectively.

[0125] The amount of ceric ammonium nitrate (IV) is 1.0 to 5.0 moleequivalent, especially 1.0 to 2.0 mole equivalent to the compound (IX).

[0126] Preferably, this step is performed in the presence of a base.Examples of a base include calcium carbonate, sodium carbonate, sodiumhydrogen carbonate or the like. The amount of a base is 1.0 to 5.0 moleequivalent, especially 1.0 to 3.0 mole equivalent to the compound (IX).

[0127] The present reaction is accomplished within several hours toseveral tens hours under −100° C. to 100° C., especially 0° C. to roomtemperature.

[0128] In the present step, a compound (IX), a base, ceric ammoniumnitrate (IV), R⁶OH and a compound of the formula: CH₂═CHOR⁶ can be addedin any order. Preferably, a compound (IX) and a compound of the formula:CH₂═CHOR⁶ are added under cooling to a solution of a base and cericammonium nitrate (IV) in a solvate of R⁶OH.

[0129] Step 9

[0130] This step is related to the preparation of an oxime derivative(compound (XI)) by reacting a ketone derivative (compound (X)) withNH₂OR² wherein R² is as defined above. This step can similarly beperformed in accordance with Step 2.

[0131] Step 10

[0132] This step is related to the preparation of a compound (XII) byreducing an oxime derivative (compound (XI)) with a reducing agent.

[0133] The present reduction should be carried out under a condition notinfluencing the group of the formula: —CH(OR⁶)₂ of the compound (XI).Preferred is a reduction under a basic condition, for example, reductionwith sodium metal in alchol.

[0134] The reaction temperature is −100° C. to 100° C., especially -50°C. to 50° C.

[0135] Step 11

[0136] This step is related to the preparation of a compound (XIII) byreacting a compound (XII) with a carboxylic acid (V) or its reactivederivative. The present step can similarly be performed in accordancewith Step 4.

[0137] Step 12

[0138] This step is related to the preparation of an aldehyde derivative(compound (VII)) by hydrolyzing a group of the formula: —CH(OR⁶)₂ of thecompound (XIII).

[0139] This hydrolysis can be carried out preferably under an acidiccondition at −100° C. to 100° C., specially 0° C. to room temperature.The reaction time is several minutes to several tens hours.

[0140] The compound (VII) prepared in this step is identical to acompound (VII) prepared in Step 5. A compound (VIII) can be preparedthrough Step 6 by using the compound (VII).

[0141] The following Examples are provided to further illustrate thepresent invention in more detail and should not be interpreted in anyway as to limit the scope thereof. The abbreviations used in theExamples have the following meanings:

[0142] Ph: phenyl;

[0143] Ac: acetyl;

[0144] TMEDA: N,N,N′,N′-tetramethylethylenediamine;

[0145] HMPA: hexamethylphosphoramide;

[0146] DMPU: N,N′-dimethylpropyleneurea;

[0147] DMI: 1,3-dimethyl-2-imidazolidinone;

[0148] CAN: ceric ammonium nitrate(IV).

EXAMPLE Reference Example 1 Preparation of (1R)-(+)-nopinone (2)

[0149]

[0150] (1R)-(+)-Nopinone (2) was prepared in accordance with the methoddescribed in J. Grimshaw, J. T. Grimshaw, and G. R. Juneja, J.Chem.Soc.,Perkin Trans. 1 1972, 50.

Example 1 Preparation of [(1R,3R,5S)-2-oxo-10-norpinan-3-yl]acetic acidethyl ester (3)

[0151]

[0152] To a solution of diisopropylamine (12.2 ml, 0.087 mol) intetrahydrofuran (60 ml) was added dropwise under −60° C. a 1.57 Msolution of n-butyllithium in hexane (55.3 ml, 0.0868 mol). Afterstirring at the same temperature for 30 minutes,1,3-dimethyl-2-imidazolidinone(DMI) (8.0 ml, 0.0732 mol) was addeddropwise thereto. To the mixture was added dropwise under −60° C. asolution of (R)-(+)-nopinone (10.0 g, 0.0724 mol) in tetrahydrofuran (10ml). The mixture was warmed to 0° C. by removing the ice bath, stirredunder ice cooling for 30 minutes, cooled at −70° C., and mixed under−60° C. with ethyl bromoacetate (24.0 ml, 0.216 mol). The mixture waswarmed to 0° C. by removing the ice bath and stirred under ice coolingfor 2 hours. To the reaction mixture were added a saturated aqueoussolution of ammonium chloride (10 ml) and ice water (150 ml) and twiceextracted with toluene (100 ml). The toluene layer was twice washed with0.5 mol dm⁻³ hydrochloric acid (100 ml) and water (50 ml) and dried overanhydrous magnesium sulfate. The solvent and excess of ethylbromoacetate were removed under reduced pressure to give 19.4 g of thetitled compound (3) as yellow oil. Yield: 119% (Crude). The compound wasused without purification.

[0153]¹H-NMR (CDCl₃, 300 MHz) δ 0.95 and 1.34 (each 3H, each s), 1.27(3H, t, J=7.01 Hz), 1.40 (1H, d, J=9.9 Hz), 1.67 (1H, m), 2.25 (1H, m),2.33-2.42 (2H, m), 2.56-2.65 (2H, m), 4.14-4.21 (2H, m).

Example 2 to 5 Preparation of [(1R,3R,5S)-2-oxo-10-norpinan-3-yl]aceticacid ethyl ester (3)

[0154] [(1R,3R,5S)-2-Oxo-10-norpinan-3-yl]acetic acid ethyl ester (3)was prepared by using the following additives (TMEDA, HMPA, DMPU) inplace of 1,3-dimethyl-2-imidazolidinone (DMI) in Example 1. The resultsare shown in Table 1. Ref. No. 1 shows the case with no additive. TABLE1

Preparations of [(1R, 3R, 5S)-2-oxo-10-norpinan-3-yl] acetic acid ethylester (3) by using an additive Ex- am- LDA Sol- BrCH₂COOC₂H₅ Ratio ofple (eq) vent Additive (eq) (3 + 3′):2 3 3′ Ref 1.2 THF none 3 4.6:1 7624 No.1 Ex. 1.2 THF TMEDA 3 5.5:1 89 11 No.2 Ex. 1.2 THF HMPA 3 7.8:1 982 No.3 Ex. 1.2 THF DMPU 3  20:1 97 3 No.4 Ex. 1.2 THF DMPU 1.5  25:1 8218 No.5

Example 6 Preparation of[(1R,3R,5S)-2-hydroxyimino-10-norpinan-3-yl]acetic acid ethyl ester (4a)

[0155]

[0156] To a solution of compound (3) (5.00 g, 0.0223 mol) in ethanol(22.5 ml) were added hydroxylamine hydrochloride (2.48 g, 0.0357 mol)and pyridine (2.82 g, 0.0357 mol). The mixture was stirred at 60° C. for2.5 hours. The reaction mixture was concentrated under reduced pressure,diluted with water, acidified with hydrochloric acid, and extracted withethyl acetate. The organic layer was washed with water and 1% aqueoussolution of sodium hydrogen carbonate, and dried over anhydrousmagnesium sulfate. The solvent was removed under reduced pressure togive 5.37 g of the titled compound (4a) as colorless oil. Yield: 100%.

[0157] [α]_(D) ²⁴+55.3° (c=1.01%, CH₃OH)

Example 7 Preparation of[(1R,3R,5S)-2-methoxyimino-10-norpinan-3-yl]acetic acid ethyl ester (4b)

[0158]

[0159] To a solution of a compound (3) prepared in the above step (19.4g, 0.0724 mol) in ethanol (80 ml) were added O-methylhydroxylammoniumchloride (7.86 g, 0.0941 mol) and pyridine (7.44 g, 0.0941 mol) andmixture was refluxed for 3 hours with stirring. The reaction mixture wasconcentrated under reduced pressure, diluted with water (50 ml) and 1mol dm⁻³ hydrochloric acid (25 ml) and twice extracted with toluene (100ml). The toluene layer was washed with water (50 ml) and 1% aqueoussolution of sodium hydrogen carbonate (50 ml), dried over anhydrousmagnesium sulfate. The solvent was removed under reduced pressure togive 18.12 g of the titled compound (4b) as yellow oil. Yield: 98.8%(Crude).

[0160] IR(Film): 1738, 1630 cm⁻¹. [α]_(D) ²⁴+69.5° (c=1.00%, CH₃OH)

Example 8 Preparation of [(1R,2R,3R,5S)-2-amino-10-norpinan-3-yl]ethanolbenzoic acid salt (5)

[0161]

Example 8-1 Preparation from Compound (4a) (Part 1)

[0162] To a suspension of lithium aluminum hydride (455 mg, 0.012 mol)in tetrahydrofuran (8 ml) was added under ice cooling aluminum chloride(533 mg, 0.004 mol) and the mixture was stirred at room temperature for30 minutes. A solution of compound (4a) (960 mg, 0.004 mol) intetrahydrofuran (2.5 ml) was added thereto dropwise under ice cooling.The mixture was stirred at room temperature for 30 minutes and refluxedfor 3 hours. To the reaction mixture was gradually added dropwise underice cooling methanol (4 ml) and water (2 ml) and refluxed with stirringfor 30 minutes. Insoluble substance was filtered and washed withmethanol. The washing solvent was mixed with the filtrate andconcentrated under reduced pressure. To the residue was added 10% brine(5 ml) and 1 mol dm⁻³ solution of sodium hydroxide (1.5 ml). The mixturewas twice extracted with ethyl acetate (15 ml). The organic layer waswashed with 10% brine (5 ml), dried over anhydrous magnesium sulfate andevaporated under reduced pressure to give 694 mg of the residue ascolorless oil. The residue was dissolved in diethylether (10 ml) and asolution of benzoic acid (462 mg, 0.00379 mol) in diethyl ether (5 ml)was added thereto and stirred. The precipitated crystal was filtered andwashed with diethyl ether to give 968 mg of benzoic acid salt ofaminoalcohol (5) as colorless crystal. Mp. 177-183° C. Yield: 79.2%.

[0163] [α]_(D) ²⁵+24.8° (c=1.00%, CH₃OH) Elemental Analysis forC₁₈H₂₇NO₃ Calculated (%): C, 70.79; H, 8.91; N, 4.59. Found (%): C,70.63; H, 8.81; N, 4.60.

Example 8-2 Preparation from Compound (4a). (Part 2)

[0164] To a suspension of lithium aluminum hydride (607 mg, 0.016 mol)in tetrahydrofuran (10 ml) was added dropwise concentraed sulfuric acid(0.42 ml, 0.008 mol) under ice cooling with stirring. The mixture wasstirred at room temperature for 1 hour. A solution of compound (4a) (963mg, 0.004 mol) in tetrahydrofuran (2.5 ml) was added thereto dropwiseunder ice cooling, and the mixture was stirred at room temperature for30 minutes and refluxed for 2 hours. To the reaction mixture wasgradually added dropwise under ice cooling methanol (4 ml), and followedby adding water (2 ml). The mixture was refluxed for 30 minutes.Insoluble substance was filtered and washed with methanol. The washingsolvent was mixed with the filtered solvent and concentrated underreduced pressure. To the residue were added 10% brine (5ml) and 1 moldm⁻³ aqueous solution of sodium hydroxide (1.5 ml). The mixture wastwice extracted with ethyl acetate (15 ml). The organic layer was washedwith 10% brine (5 ml), dried over anhydrous magnesium sulfate andevaporated under reduced pressure to give 681 mg of the residue ascolorless oil. The residue was dissolved in diethyl ether (10 ml), mixedwith a solution of benzoic acid (454 mg, 0.00372 mol) in diethyl ether(5 ml) and stirred. The precipitated crystal was filtered and washedwith diethyl ether to give 953 mg of benzoic acid salt of aminoalcohol(5) as colorless crystal. Mp. 173-182° C. Yield: 78.0%.

[0165] [α]_(D) ²⁵+25.1° (c=1.01%, CH₃OH) Elemental Analysis forC₁₈H₂₇NO₃ Calculated (%): C, 70.79; H, 8.91; N, 4.59. Found (%): C,70.56; H, 8.68; N, 4.60.

Example 8-3 Preparation from Compound (4a). (Part 1)

[0166] To a suspension of lithium aluminum hydride (4.07 g, 0.107 mol)in tetrahydrofuran (60 ml) was added under ice cooling aluminum chloride(4.77 g, 0.0358 mol). The mixture was stirred at room temperature for 30minutes. A solution of compound (4a) (9.06 g, 0.0358 mol) intetrahydrofuran (60 ml) was added thereto dropwise under ice cooling,and the mixture was stirred at room temperature for 30 minutes andrefluxed for 2 hours. To the reaction mixture was gradually addeddropwise under ice cooling methanol (60 ml), and followed by addingwater (30 ml). The mixture was refluxed for 30 minutes. Insolublesubstance was filtered and washed with methanol. The washing solvent wasmixed with the filtrate and concentrated under reduced pressure. To theresidue were added 10% brine (15 ml) and 4 mol dm⁻³ aqueous solution ofsodium hydroxide (2.6ml). The mixture was twice extracted with ethylacetate (50 ml). The organic layer was washed with 10% brine (15 ml),dried over anhydrous magnesium sulfate and evaporated under reducedpressure to give 6.09 g of the residue as colorless oil. The residue wasdissolved in diethylether (50 ml), mixed with a solution of benzoic acid(4.05 g, 0.0332 mol) in diethylether (30 ml) and stirred. Theprecipitated crystal was filtered and washed with diethylether to give8.80 g of benzoic acid salt of aminoalcohol (5) as colorless crystal.Yield: 80.5%.

[0167] IR(KBr): 3420, 2600, 1621, 1523, 1386 cm⁻¹. ¹H-NMR (CDCl₃, 300MHz) δ 0.72 (1H, d, J=9.9 Hz), 1.06 and 1.13 (each 3H, each s), 1.40(1H, m), 1.56-1.92 (3H, m), 2.12-2.36 (4H, m), 3.29 (1H, m), 3.62 (1H,m), 3.78 (1H, m), 7.32-7.47 (3H, m), 7.97-8.04 (2H, m). [α]_(D) ²⁵+23.7°(c=1.00%, CH₃OH) Elemental Analysis for C₁₈H₂₇NO₃ Calculated (%): C,70.79; H, 8.91; N, 4.59. Found (%): C, 70.57; H, 8.86; N,. 4.62.

Example 8-4 Preparation from Compound (4a). (Part 2)

[0168] To a suspension of lithium aluminum hydride (455 mg, 0.012 mol)in tetrahydrofuran (8 ml) was added dropwise under ice cooling withstirring concentrated sulfuric acid (0.32 ml, 0.006 mol). The mixturewas stirred at room temperature for 1 hour. A solution of compound (4b)(1.013 g, 0.004 mol) in tetrahydrofuran (2.5 ml) was added dropwiseunder ice cooling, stirred at room temperature for 30 minutes andrefluxed for 2 hours. To the reaction mixture was gradually addeddropwise under ice cooling methanol (4 ml), mixed with water (2 ml) andrefluxed for 30 minutes. Insoluble substance was filtered and washedwith methanol. The washing solvent was mixed with the filtrate andconcentrated under reduced pressure. To the residue were added 10% brine(5 ml) and 1 mol dm⁻³ aqueous solution of sodium hydroxide (1.5 ml). Themixture was twice extracted with ethyl acetate (15 ml). The organiclayer was washed with 10% brine (5 ml), dried over anhydrous magnesiumsulfate and evaporated under reduced pressure to give 690 mg of theresidue as colorless oil. The residue was dissolved in diethyl ether (10ml), mixed with a solution of benzoic acid (460 mg, 0.00376 mol) indiethyl ether (5 ml) and stirred. The precipitated crystal was filteredand washed with diethyl ether to give 976 mg of benzoic acid salt ofaminoalcohol (5) as colorless crystal. Mp. 175-184° C. Yield: 79.9%.

[0169] [α]_(D) ²⁵+25.3° (c=1.01%, CH₃OH) Elemental Analysis forC₁₈H₂₇NO₃ Calculated (%): C, 70.79; H, 8.91; N, 4.59. Found (%): C,70.68; H, 8.86; N, 4.61.

Example 9 Preparation of(1R,2R,3R,5S)-2-[(5-benzenesulfonyloxybenzo[b]thiophen-3-ylcarbonylamino)-10-norpinan-3-yl]ethanol(6)

[0170]

[0171] (+)-2-[(1R,2R,3R,5S)-2-Amino-10-norpinan-3-yl]ethanol benzoicacid salt (5) (5.1 g, 16.7 mmol) prepared in Example 8 was suspended inwater (10 ml). To the suspension was added 1 mol dm⁻³ HCl (17 ml) andthe deposited benzoic acid was removed by extracting with ethyl acetate.The organic layer was washed with water (10 ml). To the combined aqueouslayer was added 4 mol dm⁻³ sodium hydroxide (9.2 ml, 36.8 mmol) underice-cooling, and a solution of5-benzenesulfonyloxybenzo[b]thiophene-3-carbonyl chloride (5.89 g, 16.7mmol) in tetrahydrofuran (36 ml) was then added dropwise over 15 minuteswith stirring. After stirring for another 1 hour at the sametemperature, 1 mol dm⁻³ hydrochloric acid (4 ml) was added and extractedwith ethyl acetate. The organic layer was washed with water, dried overanhydrous magnesium sulfate and then the solvent was distilled underreduced pressure to provide 8.00 g (95.6%) of the title compound (6) ascolorless amorphous.

[0172]¹H NMR (CDCl₃, 300 MHz) δ 0.96 (1H, d, J=9.9 Hz), 1.12 and 1.26(each 3H, each s), 1.50-2.42 (9H, m), 3.69-3.82 (2H, m), 4.30 (1H, m),6.21 (1H), d, J=8.1 Hz), 7.06 (1H, dd, J=2.4 and 8.7 Hz), 7.51-7.56 (2H,m), 7.67 (1H, m), 7.73 (1H, d, J=8.7 Hz), 7.85-7.88 (2H, m), 7.88 (1H,s), 8.06 (1H, d, J=2.4 Hz)

[0173] [α]_(D) ²⁵+35.7° (c=1.00%, CH₃OH)

Example 10 Preparation of(1R,2R,3R,5S)-3-formylmethyl-2-[(5-benzenesulfonyloxybenzo[b]thiophen-3-ylcarbonylamino)-10-norpinan-3-yl](7) (Part 1)

[0174]

[0175] The compound (6) (9.72 g, 18.3 mmol) was dissolved in ethylacetate (70 ml). To the solution were added TEMPO (2, 2, 6,6-tetramethylpiperidine-1-oxyl, 14.3 mg, 0.005 equivalent) and potassiumbromide (218 mg, 0.1 equivalent). 0.41 mol dm⁻³ Aqueous sodiumhypochlorite (45 ml of a solution adjusted to pH 9.5 with sodiumhydrogen carbonate, 1 mole equivalent) was added dropwise over 3 minuteswith stirring while maintaining the inner temperature at −1° C.-6° C.After 10 minutes at this temperature, the two layers were separated andthe aqueous layer was extracted with ethyl acetate. The organic layerwas washed with water, dried over anhydrous magnesium sulfate and thenthe solvent was distilled under reduced pressure to provide 9.10 g(100%) of the title compound (7) as colorless amorphous.

[0176] IR (CHCl₃); 3443, 3093, 3066, 3030, 3016, 2925, 2871, 2828, 2729,1720, 1655, 1599, 1558, 1513, 1377 cm⁻¹ ¹H NMR (CDCl₃, 300 MHz) δ0.97(1H, d, J=10.2 Hz), 1.17 and 1.28 (each 3H, each s), 1.46 (1H, m),2.03 (1H, m), 2.22 (1H, m), 2.36-2.60 (3H, m), 2.69 (1H, ddd, J=1.2, 8.7and 17.4 Hz), 3.14 (1H, dd, J=4.5 and 17.4 Hz), 4.28 (1H, m), 6.18 (1H,d, J=8.1 Hz), 7.09 (1H, dd, J=2.4 and 8.7 Hz), 7.50-7.55 (2H, m), 7.67(1H, m), 7.75 (1H, d, J=8.7 Hz), 7.85-7.89 (2H, m), 7.89 (1H, s), 8.03(1H, d, J=2.4 Hz), 9.80 (1H, d, J=1.2 Hz) [α]_(D) ²⁵+31.8° (c=1.00%,CH₃OH)

Example 11 Preparation of(1R,2R,3R,5S)-3-formylmethyl-2-[(5-benzenesulfonyloxybenzo[b]thiophen-3-ylcarbonylamino)-10-norpinan-3-yl](7) (Part 2)

[0177] To a solution of dimethyl sulfoxide (3.16 ml, 44.5 mmol) indimethoxyethane (50 ml) was added at −60° C. to −65° C. oxalyl chloride(1.91 ml, 21.9 mmol). A solution of alchol (6) (7.352 g, 14.7 mmol) in1,2-benzenesulfonyloxybenzo[dimethoxyethane (58 ml) was added dropwisethereto at the same temperature. The mixture was stirred at −55° C. to−60° C. for 30 minutes, mixed with triethylamine (6.1 ml), stirred for30 minutes and warmed up to room temperature by removing ice bath. Thereaction mixture was diluted with water (100 ml) and extracted withtoluene. The organic layer was washed with water, dried over anhydrousmagnesium sulfate and evaporated under reduced pressure. The obtainedresidue was chromatographed on silica gel (hexane:ethyl acetate=5:5 to4:6) to give 7.32 g of the titled compound (7) described above ascolorless amorphousness. Yield: 100%.

Example 12 Preparation of(5Z)-7-[(1R,2R,3S,5S)-2-(5-benzenesulfonyloxybenzo[b]thiophen-3-ylcarbonylamino)-10-norpinan-3-yl]-5-heptenoicacid (8)

[0178]

[0179] 4-Carboxybutyltriphenylphosphonium bromide (12.17 g, 27.5 mmol)and potassium t-butoxide (7.19 g, 64.1 mmol) were suspended intetrahydrofuran (64 ml) and the mixture was stirred under ice-coolingfor 1 hour. To the reaction mixture was added a solution of compound (7)(9.11 g, 18.3 mmol) in tetrahydrofuran (27 ml) over 15 minutes, andstirring was continued for 2 hours at the same temperature. The reactionmixture was diluted with water (80 ml) and washed with toluene (2×10⁵ml). After the aqueous layer was adjusted to pH 8.1 with 5 Nhydrochloric acid (4.8 ml), anhydrous calcium chloride (8.1 g, 73 mmol)dissolved in water (16 ml) was added and the mixture was extracted withethyl acetate (2×100 ml). To the organic layer was added water (100 ml)and the aqueous layer was adjusted to below pH 2 with 5 N hydrochloricacid and extracted with ethyl acetate. The organic layer was washed withwater, dried over anhydrous magnesium sulfate and then the solvent wasdistilled off under reduced pressure to provide 11.06 g of the compound(8), which was used without purification.

Example 13 Preparation of(5Z)-7-[(1R,2R,3S,5S)-2-(5-hydroxybenzo[b]thiophen-3-ylcarbonylamino)-10-norpinan-3-yl]-5-heptenoicacid (9)

[0180]

[0181] The compound (8) (11.06 g, 18.3 mmol) prepared in above (3) wasdissolved in dimethyl sulfoxide (22 ml). To the solution was added 4 Nsodium hydroxide (27.5 ml), and the mixture was heated at 55° C. for 2hours with stirring. The reaction mixture was diluted with water (130ml) and washed with toluene (2×65 ml). The aqueous layer was acidifiedwith 5 N hydrochloric acid and then extracted with ethyl acetate. Theorganic layer was washed with water, dried over anhydrous magnesiumsulfate and then the solvent was distilled under reduced pressure toprovide 8.26 g of the crude desired compound (9). The product wasdissolved in methanol (40 ml) and water (16 ml), and the mixture wasseeded and gradually cooled with stirring. The deposited crystals werefiltered and washed with water: methanol (2:5) to provide 6.35 g of thedesired compound (9). Yield: 78.6%. The crystals were dissolved inmethanol (40 ml), and water (12 ml) was added with stirring over 7minutes. After adding seeds, the solution was continuously stirred at25° C. for 1 hour. Additional water (7 ml) was added over 40 minutes andstirring was continued for 1.5 hours at 25° C. The deposited crystalswere filtered and washed with water: methanol (3:5) (8 ml) to provide6.14 g of the almost colorless desired compound (9). Yield: 76.0%, mp145-146° C.

[0182] IR (Nujol); 3313, 3096, 3059, 3001, 1717, 1627, 1603, 1548, 1469,1440 cm⁻¹ ¹H NMR (CDCl₃, 300 MHz) δ 1.02 (1H, d, J=10.2 Hz), 1.12 and1.24 (each 3H, each s), 1.56-2.55 (14H, m), 4.29 (1H, m), 5.32-5.51 (2H,m), 6.20 (1H, d, J=9.3 Hz), 7.01 (1H, dd, J=2.4 and 9.0 Hz), 7.66 (1H,d, J=9.0 Hz), 7.69 (1H, s), 8.03 (1H, d, J=2.4 Hz) [α]_(D)²⁵=50.7°(c=1.01,CH₃OH) Elemental Analysis for C₂₅H₃₁NO₄S Calculated (%):C, 68.00; H, 7.08; N, 3.17; S, 7.26; Found (%): C, 67.84; H, 7.08; N,3.24; S, 7.31;

Example 14 Preparation of (1R)-nopinonetrimethylsilylenolether (10)

[0183]

[0184] To a solution of 1.0 g (7.24 mmol) of (1R)-(+)-nopinone (2) in 10ml of tetrahydrofuran under nitrogen atmosphere was gradually added at−78° C. 5.4 ml (10.8 mmol) of 2M solution of lithium diisopropylamide intetrahydrofuran. After 10 minutes, the mixture was warmed to 0° C. andstirred for 30 minutes. Then, the reaction mixture was cooled to −78° C.2.8 ml (22.1 mmol) of chlorotrimethylsilane was added thereto andstirred for 1 hour. The mixture was mixed at −78° C. with saturatedsodium hydrogen carbonate and warmed to room temperature. The waterlayer was extracted three times with hexane. The combined organic layerwas washed with saturated aqueous solution of ammonium chloride andsaturated brine, dried over anhydrous magnesium sulfate and evaporatedunder reduced pressure. The obtained residue was chromatographed onsilica gel (hexane : ethylacetate=9:1) to give 1.25 g of the titledcompound (10) as pale yellow oil. Yield: 82%.

[0185]¹H-NMR (CDCl₃, 300 MHz) δ 0.19 (9H, s), 0.93 (3H, s), 1.28 (3H,s), 1.30 (1H, m), 1.96-2.25 (4H, m), 2.39 (1H, dt, J=8.4 and 5.7 Hz),4.56 (1H, m). IR(CHCl₃): 1605, 1247 cm⁻¹. [α]_(D) ²⁵−15.1±0.6°(c=1.00,CHCl₃)

Example 15 Preparation of[(1R,3R,5S)-2-oxo-10-norpinan-3-yl]acetaldehyde diethyl acetal

[0186]

[0187] To 2.0 ml of ethyl alcohol were added under nitrogen atmosphere0.357 g (3.57 mmol) of calcium carbonate and 1.30 g (2.37mmol) of cericammonium nitrate (IV). To the solution was added dropwise for 5 minutesunder ice cooling a solution of 0.25 g (1.19 mmol) of compound (10) in2.30 ml (23.76 mmol) of ethyl vinyl ether. After stirring for 3 hours,the solution was warmed to room temperature. After 15 hours, thesolution was filtered through the celite, mixed with water, andextracted three times with ethyl acetate. The combined organic layer waswashed with saturated brine, dried over anhydrous magnesium sulfate,evaporated under reduced pressure. The obtained crystal waschromatographed on silica gel (hexane:ethylacetate 9:1) to give 0.1415 gof the titled compound (11) as pale yellow oil. (11:2=68:32)

[0188]¹H-NMR(CDCl₃, 300 MHz) δ 0.90 (3H, s), 1.21 (3H, t, J=7.2 Hz),1.22 (3H, t, J=7.2 Hz), 1.35-1.82 (3H, m), 2.22-2.35 (4H, m), 2.46-2.61(4H, m), 3.47-3.74 (5H, m), 4.71 (1H, t, J=6.3 Hz). IR(CHCl₃): 2929,1699, 1473, 1456, 1444, 1389, 1373, 1346, 1317, 1296, 1198, 1061, 1016cm⁻¹. [α]_(D) ²⁵+31.2±0.7°(c=1.00, CHCl₃) Elemental Analysis forC₁₅H26O₃ 0.1H₂O Calculated (%): C, 70.33; H, 10.31. Found (%): C, 70.46;H, 10.21.

[0189] Industrial Applicability

[0190] The present invention provides a process for the safe, efficient,and low cost preparation of a bicyclic aminoalcohol (compound (IV)) fromnopinone (compound (I)), resulting in inexpensive production of a PGD₂receptor antagonist, compound (VIII).

1. A process for the preparation of a compound (II):

wherein R¹ is alkyl, which comprises reacting a compound (I):

with XCH₂COOR¹ wherein X is halogen, and R¹ is as defined above in the presence of an additive and a base.
 2. A process for the preparation of a compound (IV):

which comprises reducing a compound (III):

wherein R¹ is as defined above, and R² is hydrogen or alkyl, with an aluminum hydride,
 3. A process for the preparation of a compound (IV):

which comprises reacting a compound (II):

wherein R¹ is as defined above, with NH₂OR² wherein R² is as defined above to give a compound (III):

wherein R¹ and R² are as defined above, and reducing the compound (III) with an aluminum hydride.
 4. A process for the preparation of a compound (III):

wherein R¹ and R² are as defined above, which comprises preparing a compound (II):

wherein R¹ is as defined above, through the process according to claim 1, and reacting the compound (II) with NH₂OR² wherein R² is as defined above.
 5. A process for the preparation of a compound (IV):

which comprises preparing a compound (III):

wherein R¹ and R² are as defined above through the process according to claim 4, and reducing the compound (III) with an aluminum hydride.
 6. The process according to any one of claims 2, 3 or 5 wherein the aluminum hydride is prepared by reacting a Lewis acid with lithium aluminum hydride or reacting concentrated sulfuric acid with lithium aluminum hydride.
 7. A process for the preparation of a compound (IX):

wherein R⁵ each is independently alkyl, which comprises reacting a compound (I):

with (R⁵)₃SiX wherein R⁵ is as defined above, and X is halogen, in the presence of a base.
 8. A process for the preparation of a compound (X):

wherein R⁶ each is independently alkyl, which comprises reacting a compound (IX):

wherein R⁵ each is independently alkyl, with CH₂═CHOR⁶ wherein R⁶ is as defined above in the presence of ceric ammonium nitrate (IV) in a solvate of R⁶OH wherein R⁶ is as defined above.
 9. A process for the preparation of a compound (X):

wherein R⁶ is as defined above, which comprises preparing a compound (IX):

wherein R⁵ is as defined above through the process according to claim 7, and reacting the compound (IX) with CH₂═CHOR⁶ wherein R⁶ is as defined above in the presence of ceric ammonium nitrate (IV) in a solvent of R⁶OH wherein R⁶ is as defined above.
 10. A process for the preparation of a compound (VI):

wherein R³ is hydrogen, alkyl, acyl, alkylsulfonyl or arylsulfonyl, which comprises preparing a compound (IV):

through the process according to any one of claims 2, 3, 5 and 6, and reacting the compound (IV) or its salt with a compound (V):

wherein R³ is as defined above or its reactive derivative.
 11. A process for the preparation of a compound (VII):

wherein R³ is as defined above, which comprises preparing a compound (VI):

wherein R³ is as defined above through the process according to claim 10, and oxidizing the compound (VI).
 12. A process for the preparation of a compound (VII):

wherein R³ is as defined above, which comprises preparing a compound (X):

wherein R⁶ is as defined above through the process according to claim 8 or 9, reacting the compound (X) with NH₂OR² wherein R² is as defined above to give a compound (XI):

wherein R² and R⁶ are as defined above, reducing the compound (XI) to give a compound (XII):

wherein R⁶ is as defined above, reacting the compound (XII) with a compound (V):

wherein R³ is as defined above or its reactive derivative to give a compound (XIII):

wherein R³ and R⁶ are as defined above, and reacting the compound (XIII) with an acid.
 13. A process for the preparation of a compound (VIII):

wherein R³ is as defined above, R⁴ is hydrogen or alkyl, and a double bond represents E- or Z-configuration, a pharmaceutically acceptable salt or hydrate thereof, which comprises preparing a compound (VII):

wherein R³ is as defined above through the process according to claim 11 or 12, reacting the compound (VII) with an ylide of the formula: Ph₃P═CH(CH₂)₃COOR⁴ wherein R⁴ is as defined above, and if desired, deprotecting. 